scholarly journals Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition

2011 ◽  
Vol 301 (4) ◽  
pp. H1266-H1275 ◽  
Author(s):  
Sarah A. Hale ◽  
Lindsey Weger ◽  
Maurizio Mandala ◽  
George Osol
Keyword(s):  
Nitric Oxide ◽  
Uterine Artery ◽  
Vascular Wall ◽  
Female Rats ◽  
Uterine Arteries ◽  
Tissue Inhibitors Of Metalloproteinase ◽  
No Signaling ◽  
Underlying Mechanisms ◽  
Uterine Circulation ◽  
Endothelial Nitric Oxide

Recent findings indicate that endothelial nitric oxide (NO) plays a key role in uterine artery outward circumferential remodeling during pregnancy. Although the underlying mechanisms are not known, they likely involve matrix metalloproteinases (MMPs). The goal of this study was to examine the linkage among NO inhibition, expansive remodeling, and MMP expression within the uterine vascular wall. Adult female rats were treated with NG-nitro-l-arginine methyl ester [l-NAME (LPLN)] beginning on day 10 of pregnancy and until death at day 20 and compared with age-matched controls [late pregnant (LP)]. Mean arterial pressure of LPLN rats was significantly higher than controls. LPLN fetal and placental weights were significantly reduced compared with controls. Main uterine arteries (mUA) were collected to determine dimensional properties (lumen area and wall thickness), collagen and elastin content, and levels of endothelial nitric oxide synthase (eNOS) and MMP expression. Circumferential remodeling was attenuated, as evidenced by significantly smaller lumen diameters. eNOS RNA and protein were significantly (>90%) decreased in the LPLN mUA compared with LP. Collagen and elastin contents were significantly increased in LPLN rats by ∼10 and 25%, respectively, compared with LP ( P < 0.05). Both MMP-2 and tissue inhibitors of metalloproteinase-2 as assessed by immunofluorescence were lower in the endothelium (reduction of 60%) and adventitia (reduction of 50%) of LPLN compared with LP mUA. Membrane bound MMP-1 (MT1-MMP) as assessed by immunoblot was significantly decreased in LPLN. These data suggest a novel contribution of MMPs to gestational uterine vascular remodeling and substantiate the linkage between NO signaling and gestational remodeling of the uterine circulation via altered MMP, TIMP-2, and MT1-MMP expression and activity.

scholarly journals The Piezo1 cation channel mediates uterine artery shear stress mechanotransduction and vasodilation during rat pregnancy

2018 ◽  
Vol 315 (4) ◽  
pp. H1019-H1026 ◽  
Author(s):  
Liam John ◽  
Nga Ling Ko ◽  
Alexander Gokin ◽  
Natalia Gokina ◽  
Maurizio Mandalà ◽  
...  
Keyword(s):  
Shear Stress ◽  
Uterine Artery ◽  
Cation Channel ◽  
No Production ◽  
Cell Sheets ◽  
Uterine Arteries ◽  
Intracellular Ca ◽  
No Signaling ◽  
Endothelial Shear Stress ◽  
Uterine Circulation

During mammalian pregnancy, the uterine circulation must undergo substantial vasodilation and growth to maintain sufficient uteroplacental perfusion. Although we and others have shown that nitric oxide (NO) is a key mediator of these processes, the mechanisms that augment uterine artery NO signaling during gestation have not been identified. We hypothesized that Piezo1, a recently discovered cation channel, may be involved in the process of shear stress mechanotransduction, as other studies have shown that it is both mechanosensitive and linked to NO production. Surprisingly, there are no studies on Piezo1 in the uterine circulation. Our aims in the present study were to determine whether this novel channel is 1) present in uterine arteries, 2) regulated by gestation, 3) functionally relevant (able to elicit rises in intracellular Ca2+ concentration and vasodilation), and 4) linked to NO. Immunohistochemistry confirmed that Piezo1 is present in uterine arteries, primarily but not exclusively in endothelial cells. Western blot analysis showed that its protein expression was elevated during gestation. In pressurized main uterine arteries, pharmacological activation of Piezo1 by Yoda1 produced near maximal vasodilation and was associated with significant increases in intracellular Ca2+ concentration in endothelial cell sheets. Shear stress induced by intraluminal flow produced reversible vasodilations that were inhibited >50% by GsMTx-4, a Piezo1 inhibitor, and by Nω-nitro-l-arginine methyl ester/ Nω-nitro-l-arginine, inhibitors of NO synthase. These findings are the first to implicate a functional role for Piezo1 in the uterine circulation as a mechanosensor of endothelial shear stress. Moreover, our data demonstrate that Piezo1 activation leads to vasodilation via NO and indicate that its molecular expression is upregulated during pregnancy. NEW & NOTEWORTHY This is the first study to highlight Piezo1 in the uterine circulation. As a potentially important endothelial mechanosensor of shear stress, Piezo1 may be linked to mechanisms that support increased uteroplacental perfusion during pregnancy. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/piezo1-mechanotransduction-in-the-uterine-circulation/ .

The Effect on Health of Some Cardiovascular Risk Factors

2017 ◽  
Vol 68 (10) ◽  
pp. 2237-2242
Author(s):  
Germaine Savoiu Balint ◽  
Mihaiela Andoni ◽  
Ramona Amina Popovici ◽  
Laura Cristina Rusu ◽  
Ioana Citu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Reactivity ◽  
Vascular Wall ◽  
Dose Effect ◽  
Organ Bath ◽  
Before And After ◽  
Specific Receptors ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Relaxing Response

Arterial endothelium produces a large ramge of active factors which are indispensable for modulation of vasomotor tone and maintenance of vascular wall integrity. From these factors, nitric oxide (NO), wich is released by the endothelial cells as a response to acetylcholine or adenosine action on specific receptors, plays an important role.NO is the result of oxidation process of L-arginine into L-citrulline, under the action of endothelial nitric oxide synthase (NOSe), wich is activated by intracelluar Ca2+ - calmodulin complex . Our study, performed in isolated organ bath, analyzed vascular reactivity of 12 guinea pigs� thoracic aorta rings. After phenylephrine -PHE 10-5 mol/L precontraction, the dose-effect curves for acetylcoline � ACH, adenosine 5� phosphate - 5�ADP and sodium nitroprusside � SNP were determined, before and after incubation of preparation, for 1 hour, with 5% hydrosoluble cigarettes smoke extract (CSE). Statistic analysis, performed with the use of t pair test and ANOVA parametric test, showed that incubation of vascular preparation with 5% CSE has increased the contractile response to PHE 10-5 mol/L (p[0.05), has reduced the endothelium-dependent relaxing response to ATP 10-5 mol/L (p[0.001) and 5�ADP 10-5 molo/L (p[0.001), but has not significantly modified the endothelium-independent relaxing response to SNP 10-5 mol/L (p=0.05). As a conclusion, vascular rings incubation with 5% CSE induced a decrease of endothelium NO synthesis under the action of AXH and 5�ADP, but did not change the smooth muscle fiber respomse in the presence of NO released by SNP.

Endothelial nitric oxide release in isolated perfused ovine uterine arteries: effect of pregnancy

1999 ◽  
Vol 367 (2-3) ◽  
pp. 223-230 ◽  
Author(s):  
Daliao Xiao ◽  
Youjiang Liu ◽  
William J. Pearce ◽  
Lubo Zhang
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Release ◽  
Uterine Arteries ◽  
Endothelial Nitric Oxide

scholarly journals Nitric oxide function in atherosclerosis

1997 ◽  
Vol 6 (1) ◽  
pp. 3-21 ◽  
Author(s):  
K. E. Matthys ◽  
H. Bult
Keyword(s):  
Nitric Oxide ◽  
Leukocyte Adhesion ◽  
Atherosclerotic Lesion ◽  
Vascular Wall ◽  
Early Event ◽  
No Production ◽  
Oxygen Intermediates ◽  
Atherosclerotic Lesions ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Atherosclerosis is a chronic inflammatory process in the intima of conduit arteries, which disturbs the endothelium-dependent regulation of the vascular tone by the labile liposoluble radical nitric oxide (NO) formed by the constitutive endothelial nitric oxide synthase (eNOS). This defect predisposes to coronary vasospasm and cardiac ischaemia, with anginal pain as the typical clinical manifestation. It is now appreciated that endothelial dysfunction is an early event in atherogenesis and that it may also involve the microcirculation, in which atherosclerotic lesions do not develop. On the other hand, the inflammatory environment in atherosclerotic plaques may result in the expression of the inducible NO synthase (iNOS) isozyme. Whether the dysfunction in endothelial NO production is causal to, or the result of, atherosclerotic lesion formation is still highly debated. Most evidence supports the hypothesis that constitutive endothelial NO release protects against atherogenesis e.g. by preventing smooth muscle cell proliferation and leukocyte adhesion. Nitric oxide generated by the inducible isozyme may be beneficial by replacing the failing endothelial production but excessive release may damage the vascular wall cells, especially in combination with reactive oxygen intermediates.

Endogenous Placental Estrogen Inhibition Using Letrozole in Ovine Pregnancy Lowers Uterine Artery Endothelial Nitric Oxide Production.

2008 ◽  
Vol 78 (Suppl_1) ◽  
pp. 292-292
Author(s):  
Ronald R. Magness ◽  
FuXian Yi ◽  
Steven Vang ◽  
Terrance M. Phernetton ◽  
Jason L. Austin
Keyword(s):  
Nitric Oxide ◽  
Uterine Artery ◽  
Nitric Oxide Production ◽  
Oxide Production ◽  
Endothelial Nitric Oxide

scholarly journals Can endothelial hemoglobin-α regulate nitric oxide vasodilatory signaling?

2017 ◽  
Vol 312 (4) ◽  
pp. H854-H866 ◽  
Author(s):  
Jaimit Parikh ◽  
Adam Kapela ◽  
Nikolaos M. Tsoukias
Keyword(s):  
Mathematical Modeling ◽  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Cellular Models ◽  
No Signaling ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

We used mathematical modeling to investigate nitric oxide (NO)-dependent vasodilatory signaling in the arteriolar wall. Detailed continuum cellular models of calcium (Ca2+) dynamics and membrane electrophysiology in smooth muscle and endothelial cells (EC) were coupled with models of NO signaling and biotransport in an arteriole. We used this theoretical approach to examine the role of endothelial hemoglobin-α (Hbα) as a modulator of NO-mediated myoendothelial feedback, as previously suggested in Straub et al. ( Nature 491: 473–477, 2012). The model considers enriched expression of inositol 1,4,5-triphosphate receptors (IP3Rs), endothelial nitric oxide synthase (eNOS) enzyme, Ca2+-activated potassium (KCa) channels and Hbα in myoendothelial projections (MPs) between the two cell layers. The model suggests that NO-mediated myoendothelial feedback is plausible if a significant percentage of eNOS is localized within or near the myoendothelial projection. Model results show that the ability of Hbα to regulate the myoendothelial feedback is conditional to its colocalization with eNOS near MPs at concentrations in the high nanomolar range (>0.2 μM or 24,000 molecules). Simulations also show that the effect of Hbα observed in in vitro experimental studies may overestimate its contribution in vivo, in the presence of blood perfusion. Thus, additional experimentation is required to quantify the presence and spatial distribution of Hbα in the EC, as well as to test that the strong effect of Hbα on NO signaling seen in vitro, translates also into a physiologically relevant response in vivo. NEW & NOTEWORTHY Mathematical modeling shows that although regulation of nitric oxide signaling by hemoglobin-α (Hbα) is plausible, it is conditional to its presence in significant concentrations colocalized with endothelial nitric oxide synthase in myoendothelial projections. Additional experimentation is required to test that the strong effect of Hbα seen in vitro translates into a physiologically relevant response in vivo

Exercise training improves myocardial tolerance to ischemia in male but not in female rats

2007 ◽  
Vol 293 (1) ◽  
pp. R363-R371 ◽  
Author(s):  
David B. Thorp ◽  
James V. Haist ◽  
Jennifer Leppard ◽  
Kevin J. Milne ◽  
Morris Karmazyn ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Exercise Training ◽  
Endothelial Nitric Oxide Synthase ◽  
Diastolic Pressure ◽  
Female Rats ◽  
Female Rat ◽  
Rat Hearts ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Acute exercise increases myocardial tolerance to ischemia-reperfusion (I-R) injury in male but not in female rat hearts, possibly due to a decreased heat shock protein 70 (Hsp70) response in the female hearts. This study examined whether repetitive exercise training would increase Hsp70 and myocardial tolerance to I-R injury in female rat hearts. Adaptations in myocardial manganese superoxide dismutase (MnSOD) and endothelial nitric oxide synthase (eNOS) were also assessed. Ten-week old male (M) and female (F) Sprague-Dawley rats ( n = 40 total) exercise-trained for 14 wk; the last 8 wk consisted of running 1 h at 30 m/min (2% incline), 5 days/wk. Following training, left ventricle mechanical function (LVMF) was monitored for 30 min of reperfusion following 30 min of global ischemia (Langendorff procedure). Myocardial Hsp70 content was not different in M and F control groups, while increases were observed in both trained groups (M greater than F; P < 0.05). Although MnSOD content did not differ between groups, endothelial nitric oxide synthase (eNOS) levels were decreased in F, with no change in M, following training ( P < 0.05). Hearts from control F demonstrated a greater recuperation of all indices of LVMF following I-R compared with control M hearts ( P < 0.05). Hearts of trained M exhibited improved recovery of LVMF (left ventricular diastolic pressure, left ventrcular end-diastolic pressure, +dP/d t, −dP/d t) during reperfusion compared with control M hearts ( P < 0.05). In contrast, hearts of trained F did not show any change in recovery from I-R. Hence, exercise training is more beneficial to M than F in improving myocardial function following I-R injury.

scholarly journals Alpha Globin Gene Copy Number Is Associated with Kidney Disease Among Black Individuals

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2248-2248
Author(s):  
Amy Parker Ruhl ◽  
Neal Jeffries ◽  
Yu Yang ◽  
Rakhi P. Naik ◽  
Lydia H. Pecker ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Kidney Disease ◽  
Copy Number ◽  
Globin Gene ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Alpha Globin ◽  
No Signaling ◽  
End Stage ◽  
Endothelial Nitric Oxide

Introduction: In addition to forming hemoglobin in red blood cells, alpha globin (HBA) has non-erythroid effects and is expressed in vascular endothelial cells where it interacts with endothelial nitric oxide (NO) synthase (eNOS) to limit nitric oxide diffusion across the myoendothelial junction. Reduced expression of HBA or disruption of HBA/eNOS interactions increases endothelial nitric oxide signaling. Humans have 0 to 3 copies of HBA per chromosome and Black individuals have increased variation in HBA allele count. Moreover, Black individuals are more likely to develop end-stage kidney disease (ESKD) and unexplained genetic factors may contribute to racial disparities in kidney disease not attributable to socioeconomic factors. Given that decreased endothelial NO signaling accelerates renal disease in mouse models, we hypothesized that lower HBA gene copy number would be associated with lower risk of kidney disease among Black individuals. Methods: We used droplet digital PCR to measure HBA copy number in Black individuals enrolled in the REasons for Geographic and Racial Differences in Stroke cohort. This national, prospective observational study enrolled 30,239 men and women >45 years of age from the 48 contiguous United States. Prevalent chronic kidney disease (CKD) was defined as eGFR <60 ml/min/1.73m2or urine albumin/creatinine ratio ≥30 mg/g at enrollment. Incident end-stage kidney disease (ESKD) was identified by linkage to the United States Renal Data System. The relative risk (RR) of prevalent CKD was calculated using modified Poisson multivariable regression employing a linear effect of HBA allele count and adjusting for 13 pre-specified genetic, biomedical, and socioeconomic factors. The hazard ratio (HR) for incident ESKD was calculated using Cox proportional hazards regression with the same covariates. Results: HBA copy number ranged from 2 to 6 among 9,918 Black participants (4% with 2 copies, 28% with 3, 67% with 4, and 1% with ≥ 5), with 25% of all participants having CKD at baseline. Participants were followed for a median (25th, 75thpercentile) of 10.1 (5.5, 12.5) years for the development of ESKD, with 2.4% of all participants developing ESKD. As shown in the table, after multivariable adjustment and calculated relative to the most common copy number (4), model-estimated CKD risk was 23% lower among those with 2 copies and 12% lower among those with 3 copies of HBA, while CKD risk was 14% higher among those with 5 or 6 copies of HBA. In addition, relative to 4 copies, ESKD risk was 40% lower among those with 2 copies and 22% lower among those with 3 copies, while the risk of ESKD increased by 29% in those with 5 or 6 copies of HBA. Conclusions: We identified a novel, independent genetic association of HBA copy number with CKD prevalence and ESKD incidence among Black individuals in a national, prospective cohort study in the US. The findings are consistent with our hypothesis that decreased alpha globin gene expression could increase endothelial NO signaling in small renal arteries and confer protection against renovascular injury, while increased alpha globin gene expression couldlimit endothelial NO signaling. These findings suggest that further study of the impact of HBA expression on normal renal physiology and susceptibility to injury is needed. Disclosures Naik: Elsevier: Other: Content Editor.

Sign in / Sign up

Export Citation Format

Share Document